The proposed research involves investigations of the pharmacokinetics of cyclophosphamide (CPA), isophosphamide (IPA), 4-hydroxy-CPA (HOCPA), 4-hydroxy-IPA (HOIPA), phosphoramide mustard (PM), isophosphoramide mustard (IPM), and their metabolites in mice. Correlation of blood levels of HOCPA, HOIPA, PM, and IPM arising from these drugs themselves or from CPA or IPA with antitumor response in L1210 leukemia will be attempted. Chemotherapy of (1) IPM, (2) controlled-release delivery systems for PM and IPM, and (3) combinations of CPA-PM and other CPA, IPA, PM and IPM combinations will be investigated as a means of improving therapy with these agents and as an aid in understanding their mechanism of action. The mechanism of resistance of L1210/CPA to CPA and IPA but not to PM will be investigated to test a theory of the mechanism of selectivity of CPA and IPA as antitumor agents. The objective of the proposed research is the determination of the role of HOCPA and PM and of HOIPA and IPM in chemotherapy with CPA and IPA in experimental leukemias and solid tumors. The pharmacokinetic and mechanism of action studies will utilize labeled CPA, IPA, HOCPA, HOIPA, PM, and IPM and established methodology for drug treatment, blood collection, and metabolite isolation, identification, and quantitation by TLC and radioassay. Synthesis of labeled drugs and metabolites will be by routes developed or routinely used in our laboratory. Chemotherapy studies in mice and in vitro will be performed by highly experienced personnel using established experimental tumor systems and techniques.